Isoprenylamine derivatives

ABSTRACT

A compound of the formula ##STR1## wherein R 1  is a phenethyl group, R 2  and R 3 , taken together with the nitrogen atom to which they are bonded, form an N&#39; hydroxylalkyl substituted piperazine, and (aklylene) is a lower alkylene chain substituted with a hydroxyl group; or an acid addition salt thereof is described.

This is a division of application Ser. No. 723,084 filed Apr. 15, 1985,now U.S. Pat. No. 4,658,063, which is a continuation of U.S. Ser. No.377,580 filed May 12, 1982 and now abandoned.

This invention relates to new isoprenylamine derivatives and acidaddition salts thereof, which are useful for controlling virus infectionof vertebrate animals.

There are known heretofore various substances, which have been decidedto have preventive or alleviative effects on diseases caused by viruswhose host is a vertebrate animal, or which have been recognized to becapable of alleviating symptoms of the diseases by significantlyenhancing antibody activity in the animal. Antivirotics reported so farinclude interferon, substances capable of inducing interferon, i.e.inducers (interferon inducers), and synthetic substances, such asamantadine hydrochloride or methisazone, which directly exert inhibitoryeffect on virus propagation. Interferon is glycoprotein having antiviraland antitumor activities, said glycoprotein being produced in situ bycells of a vertebrate animal when the cells are infected with virus, andhas been known to be effective in therapy of infectious viral disease aswell as of cancer. Known inducers, which induce interferon in vertebrateanimals through a process other than virus infection, include naturalhigh molecular substances such as double strand ribonucleic acid ofbacteriophage of a certain species, or synthetic high molecularsubstances such as double strand ribonucleic acid, typical of which ispolyinosinic acid-polycytidylic acid, or low molecular inducers such astilorone.

In the production of interferon, however, there is involved a problemhow to carry out purification thereof, and in fact, no economicalprocess for the production thereof has not been established yet. On theother hand, conventional interferon inducers have not been put topractical use mainly because of toxicity thereof. Synthetic antiviralagents which directly exert inhibitory effect on virus propagation,which are commercially available at present, have a rather narrow rangeof virus-infected diseases which are curable by administration of saidagents, and thus the advent of novel synthetic antiviral agents isearnestly desired. Taking such circumstances into consideration, thepresent inventors extensively conducted studies in finding compoundscapable of producing interferon of high potency and, moreover, havingantiviral activity on the biological level, and as the result they haveeventually found that compounds represented by the general formula (I)and acid addition salts thereof show excellent interferon-inducingability and, at the same time, demonstrate excellent antiviral activityeven in the biological test.

Thus, the present invention is to provide a new class of anisoprenylamine derivative represented by the following general formula##STR2## wherein at least one or two of R₁, R₂ and R₃ represent ##STR3##(in which n represents an integer of 2 to 10, and A and B areindividually hydrogen atoms or may jointly form a linking group, andwhen n is 4, A and B may be a combination of the aforesaid two cases),or R₂ and R₃ may, together with the adjacent nitrogen atom, form a1,7,10,16-tetraoxa-4,13-diazacyclo-octadecane ring, and the remainder ofR₁, R₂ and R₃ may be hydroxyethyl, phenyl, benzyl, nucleicallysubstituted benzyl, phenethyl, nucleically substituted phenethyl,-hydroxyphenethyl or phenylbutyl or a group of the formula ##STR4## (inwhich "Alkylene" is a lower alkylene chain which may behydroxy-substituted, R_(a) and R_(b), which may be the same ofdifferent, represent hydrogen, hydroxyethyl, lower alkyl or optionallynucleically substituted benzyl, or R_(a) and R_(b) may be a divalentresidue which, together with the adjacent nitrogen atom, formN'-hydroxy-substituted piperazine), and acid addition salts thereof. Forthe production of isoprenylamine derivatives represented by theabove-mentioned general formula (I) and acid addition salts thereof,there may be adopted the known procedure in which isoprenyl alcohol(e.g. decaprenol, solanesol, phytol or geraniol) represented by thegeneral formula ##STR5## wherein A, B and n are as defined above, isfirst converted into a corresponding halide (e.g. geranyl bromide,solanesyl bromide, phytyl bromide or decaprenyl bromide) or arylsulfonicacid ester (e.g. decaprenyl tosylate or solanesyl tosylate) and theresulting halide or ester is then allowed to react in the presence orabsence of a base with a compound represented by the general formula##STR6## wherein R₂ and R₃ are as defined above. This reaction isusually carried out in an organic solvent. Preferably usable as organicsolvents in the reaction are common solvents such as methanol, ethanol,chloroform, isopropyl ether, benzene and ethyl acetate. In the practiceof the above-mentioned reaction, it is preferable that a large excess ofan amino compound represented by the general formula (III) is used, orthe reaction is carried out at a temperature ranging from roomtemperature up to 100° C. in the presence of a base (e.g. sodiumhydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate). After the completion of the reaction, a desiredisoprenylamine derivative can be obtained by treating the resultantreaction liquid according to usual isolation and purification proceduressuch as extraction, concentration, column chromatography,crystallization and the like.

For the production of compounds represented by the general formula (I),which compounds contain a primary or secondary amino group, there mayalso be adopted another process in which a compound represented by thegeneral formula

    R'COX                                                      (IV)

wherein R' is a phenyl, substituted phenyl or benzyl group and X ishalogen, is allowed to undergo reaction at 0°-50° C. in the presence ofa base (such tertiary amine, e.g. pyridine and triethylamine) to obtainan acylated compound and the thus obtained N-acylated compound is thenreduced with a reducing agent (e.g. lithium aluminum hydride). Thisreduction reaction is suitably carried out at a temperature ranging fromroom temperature up to 60° C. in such organic solvent as tetrahydrofuranor ether. After completion of the reaction, a desired isoprenylaminederivative can be produced by treating the resultant reaction liquidaccording to usual isolation and purification procedures such asextraction, concentration, column chromatography, crystallization andthe like.

Further, of the compounds represented by the general formula (I), thosein which one or two of R₁, R₂ and R₃ represent a group ##STR7## whereinR_(a) and R_(b) are as defined above can be produced even by thefollowing process. That is, such compounds as referred to above areproduced by reacting the aforementioned halide or arylsulfonic acidester in the presence or absence of a base with a compound representedby the general formula

    H.sub.2 N--R'                                              (V)

wherein R' represents a substituted or unsubstituted benzyl orsubstituted or unsubstituted phenethyl group, to obtain a compoundrepresented by the general formula ##STR8## wherein R', A, B and n areas defined above, then reacting the resulting compound in the presenceor absence of a base with a compound represented by the general formula##STR9## wherein X represents halogen, to obtain a compound representedby the general formula ##STR10## wherein A, B, n and R' are as definedabove, and then reacting the resulting compound with an amino compoundrepresented by the general formula ##STR11## wherein R_(a) and R_(b) areas defined above. The above-mentioned reaction, in which the compoundrepresented by the general formula (XI) is used as a reactant, ispreferably carried out by using a large excess of said compound in analcoholic solvent (e.g. methanol or ethanol) or in the absence of anysolvent. This reaction is suitably carried out at a temperature rangingfrom room temperature up to 100° C. After the completion of thereaction, a desired isoprenylamine derivative can be obtained bytreating the resultant reaction liquid according to usual isolation andpurification procedures such as extraction, concentration, columnchromatography, crystallization and the like. An acid addition salt ofthe isoprenylamine derivative thus obtained can be obtained by mixingsaid derivative in an appropriate solvent (e.g. acetone or ethylacetate) with a desired acid to form a salt and applying such means asconcentration, crystallization or the like to the salt. The acidaddition salts suitable for use as medicines include, for example, thosewith hydrochloric acid, acetic acid, citric acid, fumaric acid, lacticacid and the like.

Illustrated below are preparative examples of isoprenylamine derivativesof the present invention.

PREPARATIVE EXAMPLE 1N-decaprenyl-N-(2-hydroxy-2-phenylethyl)ethanoloamine hydrochloride

To an ethanol solution (100 ml) containingN-(2-hydroxy-2-phenylethyl)ethanolamine (16.4 g) an isopropyl ethersolution (100 ml) containing decaprenyl bromide (20 g) was addeddropwise at room temperature for 1 hour with stirring. The mixture wasstirred at room temperature for 3 hours and heated under reflux foradditional 1 hour with stirring. After cooling, the reaction liquid wascharged with a 5% aqueous sodium hydroxide solution (100 ml) andextracted with isopropyl ether. The extract was washed with water andsaturated saline, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The concentrate (18.1 g) waschromatographed with a chloroform-ethyl acetate mixture over a columnpacked with silica gel (200 g) to obtain an oily product (15.3 g). Thisoily product was dissolved in aceton (50 ml), weakly acidified with anether solution of hydrogen chloride and allowed to stand overnight in arefrigerator. The crystallized mass was separated by filtration anddried to obtain N-decaprenyl-N-(2-hydroxy-2-phenylethyl)ethanolaminehydrochloride (13.6 g) represented by the formula mentioned below.##STR12## Given below are measured values of physical properties of thetitle compound.

Melting point: 58.6°-59.9° C.

    ______________________________________                                        N.M.R                                                                         (value in CDCl.sub.3)                                                                             (Free base):                                              ______________________________________                                        7.30                (5H, s)                                                   4.93-5.32           (10H, br)                                                 4.70                (1H, t, J=6Hz)                                            3.65                (2H, t, J=6Hz)                                            3.23                (2H, d, J=7Hz)                                            2.50-2.92           (4H, m)                                                   2.00                (36H, br-s)                                               1.59                (33H, s)                                                  ______________________________________                                    

Elementary analysis (as C₆₀ H₉₅ NO₂.HCl.1/2H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           79.37   79.58                                                 H (%)           10.76   10.79                                                 N (%)            1.54    1.53                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 2 N-(3,4-dimethoxybenzyl)disolanesylamine

To an ethanol solution (100 ml) containing 3,4-dimethoxybenzylamine (25g) an isopropyl ether solution (100 ml) containing solanesyl bromide (30g) was added dropwise at room temperature over a period of 1 hour withstirring. The mixture was stirred at room temperature for 3 hours andheated under reflux for additional 1 hour with stirring. After cooling,the reaction liquid was charged with a 5% aqueous sodium hydroxidesolution (100 ml) and extracted with isopropyl ether. The extract waswashed with water and saturated saline, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The concentrate (33.6g) was chromatographed with a chloroform-ethyl acetate solution over acolumn packed with silica gel (350 g) to obtainN-(3,4-dimethoxybenzyl)disolanesylamine (7.1 g) represented by theformula mentioned below. ##STR13## Given below are measured values ofphysical properties of the title compound.

n_(D) ²¹.5 =1.5181

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3):                                                ______________________________________                                        6.71-6.92            (3H, m)                                                  4.9-5.3              (18H, br)                                                3.83                 (6H, s)                                                  3.46                 (2H, s)                                                  3.00                 (4H, d, J=7Hz)                                           2.02                 (64H, br)                                                1.60                 (60H, s)                                                 ______________________________________                                    

Elementary analysis (as C₉₉ H₁₅₇ NO₂):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           85.34   85.59                                                 H (%)           11.36   11.51                                                 N (%)            1.01    0.97                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 3 N,N-di(3-aminopropyl)decaprenylaminetrihydrochloride

To a chloroform solution (100 ml) containing dipropylenetriamine (50 g)a chloroform solution (100 ml) containing decaprenyl bromide (40 g) wasadded dropwise at room temperature over a period of 1 hour withstirring. The resultant mixture was stirred at room temperature foradditional 3 hours. The reaction liquid was concentrated under reducedpressure to remove the chloroform therefrom and the resultingconcentrate was extracted with ethyl acetate. The extract was washedwith water and saturate saline, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain a concentrate (48.1 g).The concentrate was then dissolved in isopropyl ether (100 ml) andcharged with sodium carbonate (20 g). To the resulting mixture, whilecooling with ice-water, trifluoroacetic anhydride (30 ml) was addeddropwise over a peiord of 1 hour with stirring, and the mixture wasstirred for additional 3 hours while cooling. After the completion ofthe reaction, the reaction liquid was filtered to separate insolublesand the filtrate was concentrated under reduced pressure. Theconcentrate was charged with benzene (about 50 ml) and then concentratedunder reduced pressure. The concentrate (49.3 g) was chromatographedwith a benzene-ethyl acetate mixture over a column packed with silicagel (500 g) to obtainN,N-di(3-trifluoroacetylaminopropyl)decaprenylamine (10.1 g), which wasthen charged with an ethanol solution (100 ml) of a 10% potassiumhydroxide and heated under reflux for 1 hour. After cooling, thereaction liquid was charged with water (300 ml) and then extracted withethyl acetate. The extract was washed with water and saturated saline,dried over anhydrous sodium sulfate and concentrated under reducedpressre. The concentrate (8.9 g) was dissolved in acetone (50 ml),charged with a hydrogen chloride-ether solution to weakly acidic andthen concentrated under reduced pressure to dryness to obtainN,N-di(3-aminopropyl)decaprenylamine trihydrochloride (9.1 g)represented by the following formula. ##STR14## Given below are measuredvalues of physical properties of the tile compound.

Melting point: Caramel-like state

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                     (Free base):                                              ______________________________________                                        4.9-5.3             (10H, br)                                                 3.00                (2H, d, J=7Hz)                                            2.32-2.86           (8H, m)                                                   2.02                (36H, br)                                                 1.61                (37H, s)                                                  ______________________________________                                    

Elementary analysis (as C₅₆ H₉₇ N₃.3HCl.H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           71.57   71.66                                                 H (%)           10.94   10.81                                                 N (%)            4.47    4.13                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 4 N,N,-di(3-aminopropyl)solanesylaminetrihydrochloride

The same procedures as in Preparative Example 3 were carried out for thereaction of solanesyl bromide with dipropylenetriamine thereby toproduce N,N-di(3-aminopropyl)solanesylamine trihydrochloride of thefollowing formula. ##STR15## Given below are measured values of physicalproperties of the title compound.

Melting point: Caramel-like state

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                      (Free base):                                             ______________________________________                                        4.9-5.3              (9H, br)                                                 3.05                 (2H, d, J=7Hz)                                           2.33-2.90            (8H, m)                                                  2.00                 (32H, br)                                                1.60                 (34H, s)                                                 ______________________________________                                    

Elementary analysis (as C₅₁ H₈₉ N₃.3HCl.2H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           68.85   68.93                                                 H (%)           10.88   10.91                                                 N (%)            4.72    4.51                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 5N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine dihydrochloride

To an ethanol solution (200 ml) containing ethylendiamine (100 g) anisopropyl ether solution (200 ml) containing solanesyl bromide (89 g)was added dropwise at room temperature over a period of 2.5 hours withstirring. The resulting compound was stirred at room temperature for 3.0hours and heated under reflux for additional 1 hour with stirring. Aftercooling, the reaction liquid was charged with a 5% sodium hydroxide (200ml) and then extracted with isopropyl ether. The extract was washed withwater and saturated saline, over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The concentrate (93.2 g) wasdissolved in acetone (500 ml), charged with an ether solution ofhydrogen chloride to weakly acidic and then allowed to stand at roomtemperature overnight. The crystallized mass was separated by filtrationand dried to obtain crude N-solanesyletheylenediamine hydrochloride(47.1 g). To a chlorofrm solution (100 ml) containing the thus obtainedcrude N-solanesylethylenediamine hydrochloride (23.5 g) was addedpyridine (25 ml) and thereafter was added dropwise at room temperature achloroform solution (100 ml) containing 3,4-dimethoxybenzoyl chloride(15.0 g) over a period of 1 hour with stirring, the resulting mixturewas stirred at room temperature for additional 2.0 hours. The reactionliquid was extracted with isopropyl ether, and the extract washed withwater, 5% hydrochloric acid, 5% aqueous sodium hydrogen carbonatesolution and saturated saline, dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The concentrate (31.3 g) waschromatographed with a chloroform-ethyl acetate mixture over a columnpacked with silica gel (350 g) to obtainN-solanesyl-N,N'-bis(3,4-dimethoxybenzoyl)ethylenediamine (28.3 g). Toan anhydrous diethyl ether solution (200 ml) containingN-solanesyl-N,N'-bis(3,4-dimethoxybenzoyl)ethylenediamine was added insmall portions at room temperature lithium aluminum hydride (3.8 g) withstirring. The resulting mixture was stirred at room temperature for 1hour and then heated under reflux for 3 hours with stirring. Afterdecomposing unaltered lithium aluminum hydrided with water, the reactionliquid was extracted with isopropyl ether. The extract was washed withwater and saturated saline, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The concentrate (28.6 g) waschromatographed with a chloroform-ethyl acetate mixture over a columnpacked with silica gel (300 g) to obtain an oily product (17.5 g). Thisoily product was dissolved in acetone (500 ml), charged with an ethersolution of hydrogen chloride to weakly acidic and then allowed to standin a refrigerator overnight. The crystallized mass was separated byfiltration and then dried to obtainN-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine dihydrochloride(10.7 g) represented by the following formula. ##STR16## Given below aremeasured values of physical properties of the title compound.

n_(D) ¹⁷.5 =1.5238

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                      (Free base):                                             ______________________________________                                        6.67-6.97            (6H, br)                                                 4.82-5.51            (9H, br)                                                 3.83                 (12H, s)                                                 3.63                 (2H, s)                                                  3.48                 (2H, s)                                                  3.05                 (2H, d, J=7Hz)                                           2.55                 (4H, br)                                                 1.98                 (32H, br)                                                1.58                 (30H, s)                                                 ______________________________________                                    

Elementary analysis (as C₆₅ H₁₀₀ N₂ O₄.2HCl.H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           73.34   73.67                                                 H (%)           9.85    9.91                                                  N (%)           2.63    2.56                                                  ______________________________________                                    

PREPARATIVE EXAMPLE 6 N-solanesyl-N,N"-dibenzylethylenediaminedihydrochloride

The same procedures as in Preparative Example 5 were carried out for thereaction of solanesyl bromide with ethylenediamine to obtainN-solanesylethylenediamine and then for the reaction ofN-solanesylethylenediamine with benzoyl chloride to obtainN-solanesyl-N,N'-dibenzoylethylenediamine which was then reduced withlithium aluminum hydride to obtainN-solanesyl-N,N'-dibenzylethylenediamine dihydrochloride represented bythe following formula. ##STR17## Given below are measured values ofphysical properties of the title compound.

n_(D) ¹⁹ =1.5311

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                      (Free base):                                             ______________________________________                                        7.23                 (10H, s)                                                 4.9-5.3              (9H, br)                                                 3.65                 (2H, s)                                                  3.50                 (2H, s)                                                  3.00                 (2H, d, J=7Hz)                                           2.62                 (4H, br-s)                                               2.00                 (32H, br)                                                1.60                 (30H, s)                                                 ______________________________________                                    

Elementary analysis (as C₆₁ H₉₂ N₂.2HCl.H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           77.58   77.72                                                 H (%)           10.25   10.05                                                 N (%)            2.97    2.86                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 7N-solanesyl-N,N'-bis(3,4,5-trimethoxybenzyl)-N'-(3,4-dimethoxybenzyl)ethylenediaminedihydrochloride

The same procedures as in Preparative Example 5 were carried out for thereaction of solanesyl bromide with ethylenediamine to obtainN-solanesylethylenediamine. Subsequently, after the reaction ofN-solanesylethylenediamine with 3,4,5-trimethoxybenzoyl chloride, thereaction product was reduced with aluminum lithium hydride to obtainN-solanesyl-N,N'-bis(3,4,5-trimethoxybenzyl)ethylenediamine. Further,after the reaction ofN-solanesyl-N,N'-bis(3,4,5-trimethoxybenzyl)ethylenediamine with3,4-dimethoxybenzoyl chloride, the reaction product was reduced withlithium aluminum hydride to obtainN-solanesyl-N,N'-bis(3,4,5-trimethoxybenzyl)-N'-(3,4-dimethoxybenzyl)ethylenediaminedihydrochloride represented by the following formula. ##STR18## Givenbelow are measured values of physical properties of the title compound.

n_(D) ¹⁷.5 =1.5263

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                      (Free base):                                             ______________________________________                                        6.45-6.95            (7H, m)                                                  4.83-5.43            (9H, br)                                                 3.80,3.73            (24H, s)                                                 3.50                 (6H, s)                                                  3.02                 (2H, d, J=7Hz)                                           1.99                 (32H, br)                                                1.60                 (30H, s)                                                 ______________________________________                                    

Elementary analysis (as C₇₆ H₁₁₄ N₂ O₈.2HCl.H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           71.61   71.54                                                 H (%)           9.33    9.21                                                  N (%)           2.20    2.13                                                  ______________________________________                                    

PREPARATIVE EXAMPLE 84-[3-(N-solanesylphenythylamino)-2-hydroxypropyl]-1-piperazineethanoltrihydrochloride

To an ethanol solution (150 ml) containing phenethylamine (40 g) anisopropyl ether solution (150 ml) containing solanesyl bromide (50 g)was added dropwise at room temperature over a period of 1 hour withstirring. The resulting mixture was stirred at room temperature for 3hours and then heated under reflux for additional 1 hour with stirring.After cooling, the reaction liquid was charged with a 5% aqueous sodiumhydroxide solution (150 ml) and then extracted with isopropyl ether. Theextract was washed with water and saturated saline, dried over anhydroussodium sulfate and then concentrated under reduced pressure. Theconcentrate (51.8 g) was chromatographed with a chloroform-ethyl acetatemixture over a column packed with silica gel (550 g) to obtain an oilyN-phenethyl solanesylamine (31.3 g). The thus obtained N-phenethylsolanesylamine (31.3 g) and an ethanol solution (100 ml) containingepichlorohydrin (30 ml) and triethylamine (30 ml) were heated underreflux for 2 hours with stirring. The reaction liquid was extracted withisopropyl ether, washed with water and saturated saline, dried overanhydrous sodium sulfate and the concentrated under reduced pressure toobtain a concentrate (31.9 g). This concentrate (9.0 g) and an ethanolsolution (50 ml) containing 1-piperazine ethanol (10 g) were heatedunder reflux for 5 hours with stirring. After cooling, the reactionliquid was charged with water (200 ml) and then extracted with isopropylether. The extract was washed with water and saturated saline, driedover anhydrous sodium sulfate and then concentrated under reducedpressure. The concentrate (10.9 g) was chromatographed with achloroform-methanol mixture over a column packed with silica gel (150 g)to obtain an oily product (6.1 g). This oily product was dissolved inacetone (40 ml), charged with a hydrogen chloride ether solution toweakly acidic and then allowed to stand at room temperature overnight.The crystallized mass was separated by filtration and then dried toobtain 4-[3-(N-solanesylphenethylamino)-2-hydroxypropyl]-1-piperazineethanol trihydrochloride (4.3 g) represented by the following formula.##STR19## Given below are measured values of physical properties of thetitle compound.

Melting point: Caramel-like state; 212° C. (Decomposition)

    ______________________________________                                        N.M.R.                                                                        (δ value in CDCl.sub.3)                                                                     (Free base):                                              ______________________________________                                        7.14                (5H, s)                                                   4.82-5.41           (9H, br)                                                  3.43-3.92           (3H, m)                                                   2.98-3.40           (5H, m)                                                   2.40-2.9            (16H, m)                                                  1.98                (32H, br)                                                 1.58                (30H, s)                                                  ______________________________________                                    

Elementary analysis (as C₆₂ H₁₀₁ N₃ O₂.3HCl.2H₂ O):

    ______________________________________                                                      Calcd.                                                                              Found                                                     ______________________________________                                        C (%)           69.86   69.50                                                 H (%)           10.21   10.23                                                 N (%)            3.94    3.82                                                 ______________________________________                                    

PREPARATIVE EXAMPLE 9

The same procedures as in Preparative Example 2 were carried out for thereaction of a compound selected from decaprenyl bromide, solanesylbromide and geranyl bromide with a compound selected from1,7,10,16-tetraoxa-4,13-diazacyclooctadecane, dibenzylamine,N-benzylethanolamine, 3,4-dimethoxybenzylamine, 4-phenylbutylamine,p-methoxybenzylamine, N-(3-aminopropyl)diethanolamine,1-benzylpiperazine, p-aminophenethylamine and4-hydroxy3-methoxybenzylamine and thereby to produce the below-indicatedcompounds, the measured values of physical properties of which arelisted in Table 1.

In the structural formulas shown in Table 1, "D" represents decaprenylgroup, "S" represents solanesyl group, "Phy" represents phytyl group and"Ger" represents geranyl group.

    TABLE 1      N.M.R. (δ value Elementary analysis n.sub.D      /Melting in CDCl.sub.3) Free Calcd. (%) Found (%) Structural formula     Molecular formula point base C H N C H N      ##STR20##      C.sub.62 H.sub.106 N.sub.2 O.sub.4 34.2-35.3°      C. 4.83-5.30(10H,br),3.43-3.76(16H,br-s),2.53-3.27(10H,m),1.98(36H,br-s)     ,1.60(33H.s) 78.92 11.32 2.97 78.64 11.41 2.69      ##STR21##      C.sub.59 H.sub.87 N.HCl.1/2H.sub.2 O 74.9-78.0°      C. 7.10-7.52(10H,m),4.9-5.3(9H,br),3.52(4H,s), 3.00(2H,d,J=7Hz),     2.00(32H,br), 1.60(30H,s) 82.80 10.48 1.64 82.98 10.61 1.54      ##STR22##      C.sub.55 H.sub.85 NO.HCl 60.3-61.1°      C. 7.26(5H,s) 4.84-5.46(9H,br), 3.39-3.69(4H,m), 3.07(2H,d,J=7Hz),     2.61(2H,t), 2.00(32H,br),1.60(30H,s) 81.28 10.67 1.72 80.88 10.91 1.71      ##STR23##      C.sub.49 H.sub.89 NO.sub.2 n.sub.D.sup.20.5 =      1.4908 6.73-6.96(3H,m),5.30(2H,t,J=7Hz),3.86(6H,s), 3.48(2H,s),     3.02(4H,d,J=7Hz), 0.7-2.2(72H,m) 81.26 12.39 1.93 81.04 12.21 1.87      ##STR24##      C.sub.100 H.sub.159 N n.sub.D.sup.23.5 =      1.5129 7.16(5H,s),4.9-5.3(18H,br), 3.00(4H,d,J=7Hz), 2.3-2.7(4H,m),     (     1.9864H,br), 1.59(64H,s) 87.33 11.65 1.02 87.21 11.73 0.93      ##STR25##      C.sub.29 H.sub.45 NO.sub.2  6.71-6.96(3H,m),4.9-5.4(2H,m),3.83(6H,s),     3.46(2H,s), 3.00(2H,d,J=7Hz), 2.03(8H,br), 1.63(18H,br) 79.22 10.32 3.19     79.10 10.49 3.07      ##STR26##      C.sub.108 H.sub.171 NO n.sub.D.sup.23.3 =      1.5199 6.76(2H,d,J=8Hz),7.17(2H,d,J=8Hz),4.9-5.3(20H,br),3.75(3H,s),     3.45(2H,s), 2.98(4H,d,J=7Hz), 2.00(72H,br), 1.60(66H,s) 78.25 10.64 3.15     78.03 10.60 3.16      ##STR27##      C.sub.47 H.sub.82 N.sub.2 O.sub.2.1/2H.sub.2      O  3.86-5.42(8H,m),3.60(4H,t,J=6Hz),3.03(4H,d,J=7Hz),2.32-2.77(8H,m),1.9     0-2.26(24H,br),1.60(34H,br-s) 78.82 11.68 3.91 78.70 11.53 3.82      ##STR28##      C.sub.61 H.sub.96 N.sub.2.2HCl 135.4-145.2(decomp.) 7.26(5H,s),     4.9-5.3(10H,br), 3.15(2H,s),2.96(2H,d,J=7Hz), 2.46(8H,s),1.98(36H,br),     1.58(33H,s) 78.75 10.62 3.01 78.57 10.72 2.99      ##STR29##      C.sub.59 H.sub.93 NO.sub.2 65.2-66.3°      C. 7.27(5H,s), 4.85-5.50(10H,br), 3.4-3.70(4H,m), 3.13(2H,d,J=7Hz),     2.63(2H,t),2.01(36H,br), 1.57(30H,s) 85.13 11.26 1.68 85.15 11.38 1.69      ##STR30##      C.sub.108 H.sub.172 N.sub.2 n.sub.D.sup.27.5 =      1.5177 6.93(2H,d,J=8Hz),6.56(2H,d,J=8Hz),4.9-5.3(20H,br),3.10(4H,d,J=7Hz     ),2.63(4H,br-s), 1.98(72H,br), 1.58(66H,s) 86.56 11.57 1.87 86.38 11.68     1.88      ##STR31##      C.sub.108 H.sub.171 NO.sub.2.2H.sub.2 O n.sub.D.sup.27.5 = 1.5163     6.70-6.95(3H,m),4.9-5.3(20H,br),3.83(3H,s), 3.45(2H,br-s), 3.00(4H,d,J=7H     z), 2.00(36H,br), 1.59(33H,s) 83.60 11.36 0.90 83.84 11.48 0.88      ##STR32##      C.sub.110 H.sub.175 N.H.sub.2 O n.sub.D.sup.27.5 =      1.5140 7.10-7.30(5H,m),4.9-5.3(20H,br),3.00(4H,d,J=7Hz),2.3-2.7(4H,m),     1.98(72H,br), 1.59(70H,s) 86.37 11.66 0.92 86.11 11.57 1.04      ##STR33##      C.sub.110 H.sub.175 NO.sub.3 n.sub.D.sup.27.5 = 1.5162 6.70(3H,s),     4.9-5.3(20H,br), 3.83(6H,s), 3.12(4H,d,J=7Hz), 2.50-2.86(4H,m), 2.00(36H,b     r), 1.60(33H,s) 85.59 11.43 0.91 85.47 11.31 0.90

PREPARATIVE EXAMPLE 10

The same procedures as in Preparative Example 8 were carried out for thereaction of N-phenethylsolanesylamine or N-benzylsolanesylamine withepichlorohydrin, followed by the reaction with tertiary butylamine ordiethanolamine, thereby to produce the below-indicated compounds, themeasured values of physical properties of which are listed in Table 2.

                                      TABLE 2                                     __________________________________________________________________________                                      N.M.R. (δ value                                                                    Elementary analysis                                 Molecular      in CDCl.sub.3) Free                                                                      Calcd. (%)                                                                             Found (%)               Structural formula formula                                                                              n.sub.D base       C  H  N  C  H  N                 __________________________________________________________________________     ##STR34##         C.sub.64 H.sub.104 N.sub.2 O.sub.3. 2HCl.H.sub.2                                     n .sub.D.sup.27.5 = 1.5009                                                            7.24(5H,s), 4.84- 5.46(10H,br), 3.5-                                          3.9(7H,br), 3.15 (2H,d,J=7Hz), 2.30-                                          2.87(8H,m), 4.25- 4.72(2H,br), 1.98                                           (36H,br), 1.58(33H,s)                                                                    73.88                                                                            10.46                                                                            2.69                                                                             73.85                                                                            10.22                                                                            2.50               ##STR35##         C.sub.64 H.sub.102 N.sub.2 O. 2HCl.H.sub.2 O                                         n .sub.D .sup.27.5 = 1.5306                                                           7.25(5H,s), 4.85- 5.48(10H,br), 3.5-                                          3.9(3H,m), 3.13(2H, d,J=7Hz), 2.30-2.87                                       4H,m), 1.58(36H,br), 1.58(33H,s), 1.05                                        (9H,s)     76.38                                                                            10.62                                                                            2.78                                                                             76.46                                                                            10.38                                                                            2.59               ##STR36##         C.sub.60 H.sub.98 N.sub.2 O. 2HCl.H.sub.2 O                                          n .sub.D.sup.22.0 = 1.4802                                                            7.20(5H,s), 4.85- 5.46(br,9H), 3.52-                                          3.83(m,1H), 3.16(2H, d,J=7Hz), 2.4-2.90                                       m,9H), 2.00(br,32H), 1.58(s,30H), 1.08                                        (19H,s)    75.51                                                                            10.77                                                                            2.94                                                                             75.39                                                                            10.83                                                                            2.82              __________________________________________________________________________

Physiological effects of the compounds of the present invention areillustrated below in detail.

(1) Effect on mice infected vaccinia virus

Groups, each consisting of 10 ICR female mice weighing about 15 g, wereintravenously injected a dilute solution (0.1 ml) of vaccinia virus at aportion 2 cm from the base of a tail. On the 8th day after theinoculation, the number of lesions in the form of small pocks on thetail surface was counted after dyeing the tail with an ethanol solutionof 1% fluorescein and 0.5% methylene blue. Each test compound suspendedin a surfactant solution was administered intraperitoneally at a rate of50 mg/kg to the mice 24 hours before inoculation of the virus, wherebyantivirus activity of the test compound was evaluated in terms ofinhibition of tail lesions as calculated in each test group against agroup to which only the surfactant solution had been administered. Therate of tail lesion inhibition of each test compound is shown in Table3.

                  TABLE 3                                                         ______________________________________                                                                Prevention from                                                               vaccinia infection                                                            (Pock inhibi-                                         Test compound           tion rate %)                                          ______________________________________                                         ##STR37##              57.1                                                   ##STR38##              60.1                                                   ##STR39##              75.5                                                   ##STR40##              60.2                                                   ##STR41##              82.9                                                   ##STR42##              85.6                                                   ##STR43##              50.3                                                   ##STR44##              53.4                                                   ##STR45##              32.4                                                   ##STR46##              34.1                                                   ##STR47##              38.8                                                   ##STR48##              64.0                                                   ##STR49##              38.4                                                   ##STR50##              51.3                                                  ______________________________________                                    

(2) Effect on mice infected with influenza virus

Groups, each consisting of 10 ICR female mice weighing about 25 g werechallenged by nasal inhalation of influenza virus (PR-8). Each testcompound suspended in a surfactant solution was intraperitoneallyadministered at a rate of 50 mg/kg to the mice 24 hours before the virusinfection, and 5 times every other day from the second day after theinfection. The mice that survived 21 days or more after the challengewere regarded as survivors, and survival rate was obtained according tothe following equation as shown in Table 4. ##EQU1##

                  TABLE 4                                                         ______________________________________                                                              Prevention from                                                               influenza infection                                     Test compound         (Survival rate %)                                       ______________________________________                                                              30                                                       ##STR51##            40                                                       ##STR52##            20                                                       ##STR53##            70                                                       ##STR54##            60                                                       ##STR55##            40                                                      ______________________________________                                    

(3) Anti-tumor activity

Groups, each consisting of Balb/c male mice weighing about 20 g, wereintraperitoneally administered 5×10⁵ of tumor cells KN₇ -8. Each testcompound suspended in a surfactant solution was intraperitoneallyadministered (each time at a rate of 30 mg/kg) to the mice 24 hoursbefore inoculation of the tumor cells and on the second day and thefifth day after the inoculation, totalling 3 times, and the anti-tumoractivity was evaluated in terms of number of survivors on the 30th dayafter the inocultion. The number of survivors relative to each testcompound is shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                               Anti-tumor activity                                                           (Survivor on the                                       Test compound          30th day)                                              ______________________________________                                         ##STR56##             3/6                                                     ##STR57##             1/6                                                     ##STR58##             2/6                                                     ##STR59##             4/6                                                     ##STR60##             6/6                                                     ##STR61##             4/6                                                    ______________________________________                                    

(4) Toxicity

Using ddY male mice weighing 20-25 g, 50% lethal dose of each testcompound intravenously administered was obtained, the results of whichare shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                              LD.sub.50                                                                     (Intravenous adminis-                                   Test compound         tration mg/kg)                                          ______________________________________                                         ##STR62##            258                                                      ##STR63##            162                                                      ##STR64##             28                                                      ##STR65##            338                                                      ##STR66##            791                                                     ______________________________________                                    

(5) Human interferon inducing activity (in vitro)

Interferon was induced according to the method of Edward A. Havell etal. by treating normal diploid cells (fibroblast) originated from humanbeing with each test compound in the form of ethanol solution dilutedwith PBS (--), (25 n molar suspension). Using the radioisotopemicroassay method or H. Ishitsuka et al., interferon was measured interms of 3H-uridine-uptake inhibition rate. The rate of3H-uridine-uptake inhibition of each test compound as measured is shownin Table 7.

                                      TABLE 7                                     __________________________________________________________________________                                Human interferon                                                              3Huridine-uptake                                  Test compound               inhibition rate (%)                               __________________________________________________________________________     ##STR67##                  28.3                                               ##STR68##                  4.3                                                ##STR69##                  61.3                                               ##STR70##                  59.8                                               ##STR71##                  32.6                                               ##STR72##                  17.4                                               ##STR73##                  4.4                                                ##STR74##                  5.1                                                ##STR75##                  16.0                                               ##STR76##                  11.8                                               ##STR77##                  68.4                                               ##STR78##                  3.6                                                ##STR79##                  25.4                                               ##STR80##                  2.5                                                ##STR81##                  24.0                                               ##STR82##                  19.2                                              __________________________________________________________________________

(6) Anti-vaccinia virus activity (in vitro)

Virus plaque-formation inhibition rate of each test compound wasobtained by treating vero cells originated from the kidney of Africangreen monkey with the test compound suspension (the compound in the formof ethanol solution was suspended in Hanks culture liquid, 50 n molarconcentration) and the virus diluted solution. The inhibition rate ofeach test compound as measured is shown in Table 8.

                  TABLE 8                                                         ______________________________________                                                               Anti-vaccinia                                                                 virus activity                                                                (Plaque inhibition                                     Test compound          rate %)                                                ______________________________________                                         ##STR83##             10.6                                                    ##STR84##             14.1                                                   ______________________________________                                    

As is clear from the foregoing test results, the active ingredients ofthe present invention have interferon-inducing activity in vivo and, atthe same time, are low in toxicity with showing excellent antiviralactivity. In the light of the fact that the strict correlation ofinterferon activity with the individual antivirus activities is nowalways observed for the present ingredients, there is considered also apossibility that the antivirus activities of said ingredients atbiological level are concerned not only in interferon but also in otherdefensive mechanism of host. As deseases of human being caused by virus,there are known a number of symptoms, for example, herpes-infecteddiseases such as herpes simplex, influenza, measles, etc. Accordingly,when the active ingredients of the present invention are used forprevention from virus infection and for the treatment of virus-infecteddiseases, they are administered to patients by such technique involvingoral, inhalant or the like administration as well as subcutaneous,intramuscular and intravenous injection. According to the condition ofpatient such as age, symptom and route by which the ingredient isadministered, the active ingredient of the present invention is used ina dose of 0.5-20 mg/kg, preferably 3-5 mg/kg several times (2-4 times)per day.

The active ingredients of the present invention can be formulated intocompositions for medication, for example, tablets, capsules, granules,powder, liquid preparation for oral use, eye lotions, suppositories,ointments, injections and the like.

When the present active ingredients are orally administered, they may beformulated into tablets, capsules, granules or powder. These solidpreparations for oral use may contain commonly used excipients, forexample, silicic anhydride, metasilicic acid, magnesium alginate,synthetic aluminum silicate, lactose, cane sugar, corn starch,microcrystalline cellulose, hydroxypropylated starch or glycine and thelike; and binders, for example, gum arabic, gelatin, tragacanth,hydroxypropyl cellulose, or polyvinyl pyrrolidone; lubricatns, forexample, magnesium stearate, talc or silica; disintegrating agents, forexample, potato starch and carboxymethyl cellulose calcium; or wettingagents, for example, polyethylene glycol, sorbitan monooleate,polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate and thelike. In preparing soft capsules, in particular, the present activeingredients may be formulated by dissolving or suspending them inpolyethylene glycol or commonly used oily substrates such as sesame oil,peanut oil, germ oil, fractionated coconut oil such as Miglyol®, or thelike. Tablet or granule preparations may be coated according to theusual method.

Liquid preparation for oral use may be in the form of aqueous or oilyemulsion or syrup, or alternatively in the form of dry product which canbe re-dissolved before use by means of a suitable vehicle. To theseliquid preparations, there may be added commonly used additives, forexample, emulsifying aids such as sorbitol syrup, methyl cellulose,gelatin, hydroxyethyl cellulose and the like; or emulsifiers, forexample, lecithin, sorbitan monooleate, polyoxyethylene hydrogenatedcastor oil; non-aqueous vehicles, for example, fractionated coconut oil,almond oil, peanut oil and the like; or antiseptics, for example, methylp-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid. Further,these preparations for oral use may contain, if necessary,preservatives, stabilizers and the like additives.

In case where the present active ingredients are administered in theform of non-oral suppository, they may be formulated according to theordinary method using oleophilic substrates such as cacao oil orWitepsol®, or may be used in the form of rectum capsule obtained bywrapping a mixture of polyethylene glycol, sesame oil, germ oil, peanutoil, fractionated coconut oil and the like in a gelatin sheet. Therectum capsule may be coated, if necessary, with waxy materials.

When the present active ingredients are used in the form of injection,they may be formulated into preparations of oil solution, emulsifiedsolution or aqueous solution, and they may contain commonly usedemulsifiers, stabilizers or the like additives.

According to the method of administration, the above-mentionedcompositions can contain the present active ingredients in an amount ofat least 1%, preferably 5 to 50%.

The procedure of formulating the present active ingredients into variouspreparations is illustrated below with reference to pharmaceuticalexamples.

PHARMACEUTICAL EXAMPLE 1 Hard capsule preparations for oral use

A mixture of 25 g of N-(3,4-dimethoxybenzyl)disolanesylamine and 7.5 gof polyoxyethylene castor oil in acetone was mixed with 25 g of silicicanhydride. After evaporation of the acetone, the mixture was mixedfurther with 5 g of calcium carboxymethylcellulose, 5 g of corn starch,7.5 g of hydroxypropylcellulose and 20 g of microcrystalline cellulose,and 30 ml of water was added thereto and kneaded to give a granularmass. The mass was pelletized by means of a pelletizer (ECK pelletizerof Fuji Paudal Co., Japan) equipped with No. 24 mesh (B.S.) screen toobtain granules. The granules were dried to less than 5% moisturecontent and screened with No. 16 mesh (B.S.) screen. The screenedgranules were capsuled by means of a capsule filling machine so as to becontained in an amount of 190 mg per capsule.

PHARMACEUTICAL EXAMPLE 2 Soft capsule preparation for oral use

A homogeneous solution was prepared by mixing 50 g ofN-(3,4-dimethoxyphenethyl)didecaprenylamine with 130 g of polyethyleneglycol (Macrogol 400). Separately, a gelatin solution was prepared whichcontained 93 g of gelatin, 19 g of glycerin, 10 g of D-sorbitol, 0.4 gof ethyl p-hydroxybenzoate, 0.2 g of propyl p-hydroxybenzoate and 0.4 gof titanium oxide and which was used as a capsule file forming agent.The previously obtained solution, together with the capsule film formingagent, was treated with a manual type flat punching machine to obtaincapsules each having the contents of 180 mg.

PHARMACEUTICAL EXAMPLE 3 Injections

A mixture of 5 g ofN-solanesyl-N,N'-(3,4-dimethoxybenzyl)ethylenediamine dihydrochloride,an appropriate amount of peanut oil and 1 g of benzyl alcohol was made atotal volume of 100 cc by addition of peanut oil. The solution wasportionwise poured in an amount of 1 cc under asepsis operation into anampule which was then sealed.

PHARMACEUTICAL EXAMPLE 4 Injections

A mixture of 1.0 g of N-solanesyl-N,N'-dibenzylethylenediaminedihydrochloride, 5.0 g of Nikkol HCO-60 (a trade name) (hydrogenatedcastor oil polyoxyethylene-60 mols-ether), 20 g of propylene glycol, 10g glycerol and 5.0 g of ethyl alcohol was mixed with 100 ml of distilledwater and stirred. Under asepsis operation, the solution was portionwisepoured in an amount of 1.4 ml into an ampule which was then sealed.

What we claim is:
 1. A compound of the formula ##STR85## wherein R₁ is aphenethyl group, R₂ and R₃, taken together with the nitrogen atom towhich they are bonded, form an N'hydroxylalkyl substituted piperazine,and (alkylene is a lower alkylene chain substituted with a hydroxylgroup on the 2-position or a propylene moiety or an acid addition saltthereof. 2.4-[3-(N-solanesylphenethylamino)-2-hydroxypropyl]-1-piperazine-ethanoltrihydrochloride. 3.4-[3-(N-solanesylphenethylamino)-2-hydroxypropyl]-1-piperazine-ethanol.